PROJECT SUMMARY The lung is home to a population of innate lymphoid cells that establish residence early in development and are poised to produce type 2 cytokines (ILC2s). Although implicated in clearance of helminth infection and in allergy, their role in other types of lung injury is poorly understood. Similarly, their cytokine products have predominantly been studied in models of ?type 2? inflammation, despite growing evidence that they may also be critical for tissue maintenance and repair in a variety of homeostatic perturbations. In this application, we propose to use a well-established model of influenza-induced acute lung injury to uncover a role for ILC2s in tissue protection and healing. Furthermore, we will explore the hypothesis that a specific, prototypical ILC2 product, IL-13, significantly contributes to lung repair. Finally, we will compare the behavior of ILC2s to that of adaptive lymphocytes during influenza infection and subsequent recovery in order to illustrate the complementary but distinct roles of resident and recruited innate and adaptive lymphocytes. To accomplish our aims, we will use genetically engineered mouse strains developed in our lab, which allow for the powerful manipulation, phenotyping, and tracking of these fascinating cells. We will pair these novel models and tools with classic and clinically-applicable physiologic measurements to understand how phenomena of cellular biology translate to whole animal physiology. These studies will greatly expand upon current knowledge about the biology of ILC2s in influenza infection and/or other models of acute lung injury. It is an unfortunate reality of pulmonary medicine that there are relatively few effective, targeted treatments. This paucity of treatment options persists in large part because knowledge of pulmonary biology?and pulmonary immunity, specifically?are still so limited. The investigations described herein will uncover critical aspects of the biology of innate lymphoid cells and their products?knowledge that is essential to the eventual harnessing of these pathways to safely and effectively reduce and remedy acute lung injury in human patients.